5AYF

Crystal structure of SET7/9 in complex with cyproheptadine

5AYF の概要

• エントリーDOI: 10.2210/pdb5ayf/pdb
• 分子名称: Histone-lysine N-methyltransferase SETD7, S-ADENOSYLMETHIONINE, 4-(dibenzo[1,2-a:2',1'-d][7]annulen-11-ylidene)-1-methyl-piperidine, ... (5 entities in total)
• 機能のキーワード: set domain, methyltransferase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 29672.19

構造登録者

Niwa, H.,Handa, N.,Takemoto, Y.,Ito, A.,Tomabechi, Y.,Umehara, T.,Shirouzu, M.,Yoshida, M.,Yokoyama, S. (登録日: 2015-08-20, 公開日: 2016-04-27, 最終更新日: 2024-10-23)

主引用文献

Takemoto, Y.,Ito, A.,Niwa, H.,Okamura, M.,Fujiwara, T.,Hirano, T.,Handa, N.,Umehara, T.,Sonoda, T.,Ogawa, K.,Tariq, M.,Nishino, N.,Dan, S.,Kagechika, H.,Yamori, T.,Yokoyama, S.,Yoshida, M.
Identification of Cyproheptadine as an Inhibitor of SET Domain Containing Lysine Methyltransferase 7/9 (Set7/9) That Regulates Estrogen-Dependent Transcription
J.Med.Chem., 59:3650-3660, 2016

PubMed Abstract: SET domain containing lysine methyltransferase 7/9 (Set7/9), a histone lysine methyltransferase (HMT), also methylates non-histone proteins including estrogen receptor (ER) α. ERα methylation by Set7/9 stabilizes ERα and activates its transcriptional activities, which are involved in the carcinogenesis of breast cancer. We identified cyproheptadine, a clinically approved antiallergy drug, as a Set7/9 inhibitor in a high-throughput screen using a fluorogenic substrate-based HMT assay. Kinetic and X-ray crystallographic analyses revealed that cyproheptadine binds in the substrate-binding pocket of Set7/9 and inhibits its enzymatic activity by competing with the methyl group acceptor. Treatment of human breast cancer cells (MCF7 cells) with cyproheptadine decreased the expression and transcriptional activity of ERα, thereby inhibiting estrogen-dependent cell growth. Our findings suggest that cyproheptadine can be repurposed for breast cancer treatment or used as a starting point for the discovery of an anti-hormone breast cancer drug through lead optimization.

PubMed: 27088648
DOI: 10.1021/acs.jmedchem.5b01732

実験手法

X-RAY DIFFRACTION (2.005 Å)